Treatment of peripheral psoriatic arthritis

INTRODUCTION — Psoriatic arthritis (PsA) affects multiple domains, including peripheral arthritis, axial arthritis, dactylitis, enthesitis, skin, and nails. The severity of involvement ranges from mild to severe, with some patients experiencing advanced joint damage and functional disability.

Treatment of PsA requires coordinated intervention to address all domains of this disease. It is essential to thoroughly evaluate patients for involvement in each of these domains to develop a comprehensive treatment regimen. In addition, multiple comorbidities are associated with PsA and often negatively impact therapeutic response.

The choice of therapy for peripheral arthritis is based on the severity of disease and the patient's response to treatment. It may also be influenced by comorbidities, patient goals and preferences regarding cost and route of drug administration, and regulatory and insurance requirements.

The choice of treatment also depends, in part, on whether the patient has active psoriasis as well as arthritis, especially when the psoriasis has a major negative impact on the patient.

The drugs used for the peripheral arthritis of PsA overlap with the agents prescribed for other forms of inflammatory arthritis, such as spondyloarthritis and rheumatoid arthritis. However, patients with these diagnoses may experience markedly different responses to the same drugs.

The treatment of the peripheral arthritis of PsA is discussed in this topic review. The treatment of other manifestations of psoriasis and PsA, the clinical manifestations and diagnosis of PsA, and the pathogenesis of PsA are presented separately:

●(See "Treatment of psoriatic arthritis".)

●(See "Treatment of psoriasis in adults".)

●(See "Nail psoriasis".)

●(See "Clinical manifestations and diagnosis of psoriatic arthritis".)

●(See "Pathogenesis of psoriatic arthritis".)

DISEASE SEVERITY DEFINITIONS — For purposes of this topic review, we define disease severity using the groups below. However, we recognize that there is substantial heterogeneity in psoriatic arthritis (PsA) and that these definitions may not be a perfect fit for a given patient.

In particular, functional limitation is an important component to disease assessment and is highly dependent on the individual patient. The impact of the same objective findings on a patient’s quality of life may vary dramatically between patients and may depend on the patient’s vocation, treatment goals, and other issues. However, we believe that these definitions provide a useful framework for therapeutic decisions.

●Minimal disease – Patients with intermittent joint symptoms that do not significantly impact the patient’s activities.

●Mild disease – Patients with mild peripheral PsA typically fall into one of two groups:

•Patients who meet the following characteristics:

-Up to three joints affected by PsA

-No joint damage

-No significant impact on function or quality of life

•Patients with intermittent joint involvement that has failed to respond to nonsteroidal antiinflammatory drugs (NSAIDs)

●Moderate to severe disease – Patients with moderate to severe peripheral PsA typically fall into one of two groups:

•Patients with highly active disease (eg, multiple involved joints, erosive disease at presentation, functional limitation)

•Patients with a mild disease presentation who fail to improve after three months of treatment (see 'Treatment options' below)

Clinical trials frequently define treatment efficacy using American College of Rheumatology (ACR) response criteria (table 1) or the Psoriasis Area and Severity Index (PASI). These response criteria are discussed elsewhere. (See "Assessment of rheumatoid arthritis disease activity and physical function", section on 'ACR response criteria' and "Treatment of psoriasis in adults".)

MINIMAL DISEASE — For patients with minimal disease, we suggest initiating treatment with symptomatic therapies such as a nonsteroidal antiinflammatory drug (NSAID) [1,2].

●Available options – NSAIDs that we use in patients with peripheral arthritis include naproxen (375 to 500 mg twice daily), celecoxib (200 mg twice daily), ibuprofen (up to 2400 mg daily), diclofenac (up to 150 mg daily), ketoprofen (up to 200 mg daily), or meloxicam (up to 15 mg daily) (table 2). The cyclooxygenase 2 (COX-2) selective inhibitor etoricoxib can also be given in a once-daily dose of 60 or 90 mg but is not available in the United States or Canada.

●NSAID efficacy – There is general consensus by experts that NSAIDs, including both nonselective NSAIDs (eg, naproxen) and COX-2 selective NSAIDs (eg, celecoxib), can help control the mild inflammatory symptoms of psoriatic arthritis (PsA) and may also lessen pain and stiffness in spondylitis, although there is very limited evidence from randomized trials in patients with PsA [1-5].

●NSAID comparative efficacy – Comparative studies have not found any difference in efficacy between different NSAIDs. As a result, the choice of an NSAID depends upon the individual clinician's familiarity with a particular drug, patient preference regarding frequency of administration, and individual patient tolerance and comorbidities (eg, cardiovascular or peptic ulcer disease).

●NSAID contraindications – Many patients with PsA have an increased risk of cardiovascular disease. NSAIDs may add to that risk.

While there has been some concern that NSAIDs may aggravate the cutaneous manifestations of psoriasis [6,7], in one randomized trial of a COX-2 selective inhibitor, no significant difference in skin involvement was noted between the two groups [3].

Other concerns regarding the safety of NSAIDs are discussed elsewhere. (See "NSAIDs: Adverse cardiovascular effects" and "Nonselective NSAIDs: Overview of adverse effects".)

●Alternatives to NSAID – In patients with only one or two swollen joints (ie, mono- or oligoarthritis), we generally perform a joint aspiration and intraarticular glucocorticoid injection. (See "Joint aspiration or injection in adults: Technique and indications".)

Although there are no randomized trials demonstrating efficacy of intraarticular injections, an observational cohort study demonstrated that approximately 40 percent of patients with PsA will respond to intraarticular injections [8]. Care should be taken in patients who require intraarticular glucocorticoid injections to avoid injection through psoriatic plaques, which may introduce cutaneous flora into the joint [9]. We generally avoid the use of oral glucocorticoids. (See "Treatment of psoriatic arthritis", section on 'Limited role of glucocorticoids'.)

MILD DISEASE

Treatment selection — For patients with mild peripheral psoriatic arthritis (PsA), we suggest treating with apremilast or methotrexate (MTX).

We prefer apremilast because it is generally well tolerated and does not require routine monitoring. If apremilast is not feasible, we typically use MTX. In Europe, MTX is often preferred over apremilast because of its widespread availability. However, multiple options to both apremilast and MTX exist. (See 'Alternatives to apremilast' below.)

Patients may require treatment for up to three to four months to determine maximum efficacy of these agents.

We do not use apremilast, MTX, leflunomide (LEF), cyclosporine, or sulfasalazine (SSZ) for patients with joint damage due to PsA. There are no studies demonstrating that these agents are effective at preventing erosive disease due to PsA. Patients with joint erosions are classified as having moderate to severe disease and should be treated with a biologic agent. (See 'Other agents' below and 'Moderate to severe disease' below.)

Treatment options

Apremilast

●Dosing and administration – The target dose for apremilast is 30 mg twice daily. We start apremilast at 10 mg daily and then increase the dose by 10 mg every day until this target dose is reached.

●Efficacy – Apremilast is an effective therapy for peripheral PsA. In a study of 504 patients with PsA, patients randomized to receive apremilast 30 mg twice daily were significantly more likely to experience improvement in their peripheral arthritis than patients treated with placebo (40 versus 19 percent). This study also noted improvements in physical function, psoriasis, and physical function associated with apremilast therapy [10].

Apremilast may be particularly appropriate for patients with the following characteristics:

•Concomitant enthesitis and dactylitis – Apremilast has efficacy against both manifestations, particularly early in the disease course. (See "Treatment of psoriatic arthritis", section on 'Enthesitis and dactylitis'.)

•Concomitant psoriasis – The beneficial impact on skin disease appears similar to MTX, but the drugs have not been directly compared.

•Multiple comorbidities – Given the excellent safety profile of apremilast.

●Precautions – Routine laboratory monitoring is not required. However, the following precautions should be considered:

•Chronic kidney disease – The dose should be reduced to 30 mg once daily in patients with creatinine clearance estimated at less than 30 mL/min.

•Weight loss – Patients treated with apremilast should have their weight monitored regularly, as significant weight loss may require discontinuation of treatment [11].

•Depression – Use of apremilast has also been associated with an increase in reports of depression compared with placebo [12].

Alternatives to apremilast

Methotrexate

●Dosing and administration – Oral MTX is initiated at 10 mg once weekly and should be increased over the next two to four weeks to 20 mg once weekly.

In patients with an inadequate response to oral MTX greater than 17.5 mg weekly, we switch to the subcutaneous route, which improves absorption of the medication. Alternatively, splitting the oral dose into three doses administered over a 24-hour period (eg, morning, evening, and the next morning) may improve pharmacokinetics and pharmacodynamics. (See "Use of methotrexate in the treatment of rheumatoid arthritis", section on 'Dosing and administration'.)

Subcutaneous MTX can be increased up to 25 or, rarely, 30 mg weekly. With the correct dose, a response should occur within eight weeks of initiating therapy. The maximal response to MTX is usually achieved within three months of treatment with the drug. Patients who do not respond to MTX 25 mg weekly for six to eight weeks are unlikely to respond to more prolonged therapy or higher doses.

●Efficacy – Observational studies and our clinical experience indicate that MTX may be effective for some patients with peripheral PsA [13-15]. Expert opinion also supports use of MTX for the treatment of peripheral PsA, including treatment guidelines of the European Alliance of Associations for Rheumatology (EULAR; formerly known as European League Against Rheumatism) [4,16] and the Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) [5,17]. We use it as well based upon ease of use, tolerability, proven efficacy in psoriasis, and long and extensive experience from the treatment of rheumatoid arthritis.

However, most randomized trials and other studies have not shown significant benefit to MTX for the treatment of peripheral PsA. These clinical trials have all had significant limitations, including the use of lower doses of MTX than are routinely used in practice; patient populations with very longstanding disease; small numbers of subjects; trials of short duration; and other elements of poor study design [14,18].

For example, in the Study of Etanercept and Methotrexate in Subjects with Psoriatic Arthritis (SEAM-PsA Study), a randomized trial that compared MTX monotherapy with etanercept monotherapy and the combination of etanercept and MTX, MTX appeared to inhibit radiographic progression, but the magnitude of inhibition was significantly less than that observed with etanercept [18]. Furthermore, the absence of a placebo arm complicates the interpretation of these data.

●Precautions – In patients with psoriasis who have obesity or diabetes, MTX is associated with an increased risk of hepatic fibrosis [19,20]. Precautions for the use of MTX and prevention of adverse effects are discussed elsewhere. (See "Use of methotrexate in the treatment of rheumatoid arthritis", section on 'Precautions and prevention of adverse effects'.)

Other agents — For patients who are unable to use either apremilast or MTX, other reasonable options include LEF and cyclosporine. Cyclosporine has some efficacy for psoriasis and arthritis, whereas LEF generally is less beneficial for the skin disease.

We do not typically use SSZ for peripheral PsA, given limited data supporting its use for this indication and our own clinical experience [21,22].

For patients whose disease is not well controlled with one of these agents, we typically treat with a tumor necrosis factor (TNF) inhibitor. (See 'TNF inhibitors for most patients' below.)

●Leflunomide

•Dosing and administration – LEF (20 mg daily, taken orally) can also be prescribed as a first-line therapy for patients with a low skin burden of psoriasis.

We do not use a loading dose, as reported in some studies [23], because of the higher rate of gastrointestinal side effects with this approach.

•Efficacy – The benefits of LEF in patients with PsA have been shown in a small number of randomized trials and observational studies [23-27]. In our experience, LEF is effective in approximately 40 percent of patients. It also improves skin disease but may be less effective for the skin than MTX [27]. Treatment for a total of three months is usually adequate to determine the maximal degree of benefit. Effects on progression of radiologic joint damage have not been demonstrated.

•Precautions – Details regarding adverse effects associated with LEF are discussed elsewhere. (See "Pharmacology, dosing, and adverse effects of leflunomide in the treatment of rheumatoid arthritis", section on 'Adverse effects'.)

●Cyclosporine

•Dosing and administration – Cyclosporine is used in lower doses for psoriasis and PsA than for organ transplantation. Most patients receive between 2.5 and 5 mg/kg daily orally, usually divided into two to three doses daily.

•Efficacy – Evidence for the efficacy of cyclosporine for PsA includes the following:

-An open-label trial randomized 99 patients with PsA to treatment with cyclosporine (3 mg/kg daily) versus SSZ (2000 mg daily) versus "usual care" (ie, nonsteroidal antiinflammatory drugs [NSAIDs], low-dose prednisone, and analgesics). This study demonstrated only very modest benefit to cyclosporine compared with the other treatments [28].

-A blinded trial randomized 72 patients with PsA who had an incomplete response to MTX to receive either cyclosporine or placebo. The addition of cyclosporine to MTX was associated with significant improvements in the number of swollen joints and C-reactive protein compared with patients receiving placebo [29].

Cyclosporine is also an effective agent for psoriatic skin disease.

•Precautions – Use of cyclosporine has been largely supplanted by other more potent and safer therapies for the treatment of PsA. Kidney toxicity is a limiting factor, and kidney function and blood pressure need to be closely monitored. (See "Cyclosporine and tacrolimus nephrotoxicity".)

●Sulfasalazine

•Dosing and administration – SSZ is started at 500 mg daily and gradually increased over a period of several days to a maximum of 1000 to 1500 mg twice daily.

•Efficacy – The available evidence, including randomized trial data [21,30-32], suggests only limited benefit for the joint and even less for skin disease, although improvement can be seen in both domains [21,30,33-35].

The largest study of SSZ in PsA randomly assigned 221 patients with PsA to SSZ (2 g daily) or placebo [34]. Using the Psoriatic Arthritis Response Criteria (PsARC) to identify patients who responded to the medication, the response rate was higher in the SSZ group than in the placebo group (58 versus 45 percent), but the effect size was small.

•Precautions – Adverse effects may be a limiting factor for the use of SSZ. In one study, 40 percent of patients discontinued SSZ within three months [35].

The major reasons for discontinuation of therapy are gastrointestinal side effects. In addition, the onset of drug-induced lupus and toxic epidermal necrolysis has been described in patients with psoriasis treated with SSZ [36,37].

The dose of SSZ required to control PsA may be higher than the dose needed for RA. As a result, many patients with PsA do not tolerate SSZ, although it is effective in some patients [21,30,34,35].

Patients with sulfa allergy should not take SSZ. Routine monitoring of laboratory tests, as in patients with rheumatoid arthritis, is required, as SSZ may lead to leukopenia. (See "Sulfasalazine: Pharmacology, administration, and adverse effects in the treatment of rheumatoid arthritis", section on 'Adverse effects'.)

MODERATE TO SEVERE DISEASE

TNF inhibitors for most patients — For patients with moderate to severe disease, we suggest a tumor necrosis factor (TNF) inhibitor. These agents are generally the first-line therapy in this setting because of the greater experience that exists with TNF inhibitors compared with the newer agents, as well as the greater number of trials providing evidence of benefit.

This approach is also supported by the 2015 and 2021 Group for Research and Assessment of Psoriasis and Psoriatic Arthritis (GRAPPA) and the 2020 European Alliance of Associations for Rheumatology (EULAR) recommendations [4,5,38]. However, evidence is accumulating that the other biologic agents are as effective as TNF inhibitors for the peripheral joints [16,39-41].

For patients who cannot use TNF inhibitors, we use one of the other biologic agents discussed below. (See 'Failure of initial TNF inhibitor' below.)

Apremilast may also be used by patients trying to avoid biologic agents, but it may be less effective for more active disease [10,42].

●Choice of TNF inhibitor – All five of the original TNF inhibitors (etanercept, adalimumab, infliximab, certolizumab pegol, and golimumab) are available for use in patients with psoriatic arthritis (PsA) in the United States, Canada, the European Union, and many other countries.

The efficacy of the drugs for the arthritis appears comparable, and the choice of agent is based upon patient preferences for route (subcutaneous versus intravenous) and frequency of administration; regulatory and payor requirements and limitations; and potential cost to the patient.

The choice of agent should be made in collaboration with the patient's dermatologist.

In addition, the presence of uveitis or inflammatory bowel disease will influence the choice and dose of TNF inhibitor. (See "Uveitis: Treatment", section on 'Anti-tumor necrosis factor-alpha' and "Medical management of moderate to severe Crohn disease in adults", section on 'Choice of anti-TNF agent'.)

●TNF inhibitor dose and administration – The five original TNF inhibitors and common dosing regimens are listed below and summarized in the table (table 3).

•Etanercept – 50 mg as a subcutaneous injection once weekly. Etanercept is a dimeric p75 TNF-alpha receptor Fc fragment fusion protein that binds TNF. An initial dose of 50 mg twice weekly for the first three months of therapy may be used in patients requiring treatment for moderate to severe psoriasis.

•Infliximab – 5 mg/kg administered by intravenous infusion at zero, two, and six weeks, followed by 5 mg/kg every eight weeks thereafter. It should be given with methotrexate (MTX) to prevent the development of anti-drug antibodies. Infliximab is a human-mouse chimeric anti-TNF-alpha antibody.

•Adalimumab – 40 mg subcutaneously once every two weeks. It should be given with MTX to prevent the development of anti-drug antibodies. Adalimumab is a human monoclonal anti-TNF antibody.

•Golimumab – 50 mg subcutaneously once monthly. Golimumab is a human monoclonal anti-TNF antibody.

•Certolizumab pegol – Initial dose of 400 mg (administered as two 200 mg injections subcutaneously). This dose is repeated two and four weeks after the initial dose, followed by a maintenance dose of 200 mg once every other week or 400 mg every four weeks. If the patient has moderate to severe psoriasis, then the dose is 400 mg every other week. Certolizumab pegol is a pegylated Fab fragment of a humanized anti-TNF monoclonal antibody.

●Efficacy of TNF inhibitors – The efficacy of the TNF inhibitors in patients with PsA has been well documented in meta-analyses [43] and in multiple clinical trials with all of these agents, including etanercept [44-47], infliximab [6,48-52], adalimumab [53-58], golimumab [59,60], and certolizumab pegol [61,62], compared with placebo. In one retrospective analysis, monotherapy with a TNF inhibitor was superior to MTX monotherapy after controlling for multiple variables [63]. Benefits associated with TNF inhibitor therapy include:

•Improvement in arthritis, with an American College of Rheumatology (ACR) criteria for 20 percent improvement (ACR20) (table 1) response in 50 to 65 percent of patients within three months

•Reduced radiographic progression

•Improved physical function and health-related quality of life measures.

Enthesitis, dactylitis, and cutaneous findings also improved in TNF inhibitor-treated patients. (See "Treatment of psoriatic arthritis", section on 'Enthesitis and dactylitis'.)

Sustained benefit from these drugs has been shown in several drug registries and other studies [63-68]. As an example, in the Danish registry of 764 patients with PsA treated with their first TNF inhibitor in clinical practice, the median amount of time a patient remained compliant with that therapy (ie, drug survival) was 2.9 years. The ACR50 response rate was 45 percent.

In addition to improvement in clinical signs and symptoms, these agents also reduce radiographic progression of disease. A meta-analysis of five randomized trials involving 1110 patients found that significantly fewer patients with PsA who were treated with TNF inhibitors (including etanercept, adalimumab, infliximab, and golimumab) exhibited radiographic disease progression at week 24 of treatment compared with patients who received placebo (15 versus 31 percent) [69].

●Treatment considerations

•Screen for latent tuberculosis – Screening for latent tuberculosis (TB) prior to beginning therapy with anti-TNF agents is necessary, and those with evidence of disease usually require prophylactic anti-TB therapy. (See "Treatment of tuberculosis infection (latent tuberculosis) in nonpregnant adults without HIV infection".)

•Transition immunosuppression – For patients already taking an oral immunosuppressive agent (eg, apremilast, MTX), we add the TNF inhibitor to their current regimen.

However, in contrast to rheumatoid arthritis, MTX generally can be discontinued in patients with PsA who respond to TNF inhibitor therapy [18], with the exception of infliximab and adalimumab, which may induce anti-drug antibodies [70].

Evidence from registries has not shown increased efficacy with the addition of MTX to TNF inhibition. However, drug survival with combined treatment was increased slightly for most agents, most markedly for patients on infliximab [71].

•Avoid in patients at risk of multiple sclerosis – We avoid TNF inhibitors in patients with first-degree relatives with multiple sclerosis. (See "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects", section on 'Demyelinating disease'.)

Details regarding adverse effects associated with TNF inhibition are discussed elsewhere. (See "Tumor necrosis factor-alpha inhibitors: An overview of adverse effects", section on 'Adverse effects'.)

FAILURE OF INITIAL TNF INHIBITOR

Treatment selection — Initial treatment with a tumor necrosis factor (TNF) inhibitor may fail due to either an inadequate response (ie, primary non-response) or loss of efficacy (ie, secondary non-response). Patients may also need to stop TNF inhibitor therapy due to an adverse effect. Nonadherence due to cost or side effects may also contribute to an inadequate response. (See 'Initial considerations' below.)

If nonadherence is not an issue, the selection of the next therapeutic agent is based on several factors, including the reason for treatment failure and the disease domains that are most relevant for the patient.

Switch to alternative TNF inhibitor for secondary non-response — In patients whose experience loss of efficacy following an initial response to TNF inhibition (ie, secondary non-response), we switch to a second TNF inhibitor rather than trying a different class of biologic agent.

In a patient initially treated with one of the antibody-based agents (eg, infliximab, adalimumab, golimumab, or certolizumab), we prefer to switch to the soluble TNF receptor (etanercept) and vice versa.

For patients with an elevated body mass index (BMI), intravenous, weight-based dosing with infliximab or golimumab may be more effective than subcutaneous administration.

Switch to IL-17 inhibitor for primary non-response or adverse effect — In patients who fail to respond to TNF inhibition (primary non-response) or experience an adverse effect (eg, skin eruption, lupus-like reaction, demyelination, or infection), we use an interleukin 17 (IL-17) inhibitor such as secukinumab, ixekizumab, or bimekizumab. Both secukinumab and ixekizumab have been approved by the US Food and Drug Administration (FDA) for the treatment of psoriatic arthritis (PsA); bimekizumab has been approved by the FDA for the treatment of psoriasis and by the European Medicines Evaluation Agency (EMEA) for the treatment of PsA.

●Administration – These agents may be given with or without apremilast or methotrexate (MTX). Patients who are already taking apremilast or MTX should continue until the patient demonstrates a response, at which time the oral immunosuppressant may be stopped.

●Efficacy – IL-17 inhibitors have comparable efficacy for the treatment of the peripheral arthritis of PsA, and the choice of specific agent is based upon patient preferences, frequency of administration, regulatory and payor requirements and limitations, and potential cost to the patient.

IL-17 inhibitors may be more efficacious for controlling severe psoriasis than TNF inhibitors [72,73].

●Precautions – IL-17 inhibitors do not require routine monitoring if they are not concomitantly administered with oral immunosuppressive agents. We screen (and treat) patients for latent tuberculosis (TB) prior to initiating treatment with IL-17 inhibitors. However, there are no data demonstrating latent TB reactivation following IL-17 blockade. (See "Treatment of tuberculosis infection (latent tuberculosis) in nonpregnant adults without HIV infection" and "Tuberculosis infection (latent tuberculosis) in adults: Approach to diagnosis (screening)".)

Secukinumab — Secukinumab is a human anti-IL-17A monoclonal antibody that is effective for the treatment of PsA and psoriasis.

●Dosing and administration – Secukinumab is administered by subcutaneous injection, usually with a loading dose of 300 mg at weeks 0, 1, 2, 3, and 4, followed by 300 mg every four weeks.

In a trial of 258 patients with PsA, patients who received secukinumab 300 mg every four weeks (following a loading dose) were more likely to experience improvement in their clinical joint disease after 16 weeks of treatment than patients treated with placebo (52 versus 23 percent) [74]. However, secukinumab 150 mg every four weeks was not statistically better than placebo (odds ratio [OR] 1.92, 95% CI 0.89-4.15).

●Efficacy – Secukinumab has been shown to be effective by a number of measures (eg, joint and skin symptoms, radiographic damage, physical function, quality of life) for the treatment of PsA in a series of phase 3 randomized trials [75-77]. However, patients may require up to six months of therapy to achieve their maximal response.

Ixekizumab — Ixekizumab is an IL-17A monoclonal antibody that has demonstrated efficacy for psoriasis and PsA.

●Dosing and administration – Ixekizumab is administered by subcutaneous injection, without loading dose, at a dose of 80 mg every two weeks.

●Efficacy – Ixekizumab has been demonstrated to be effective for PsA in clinical trials of patients who had previously been treated with an oral immunosuppressive agent or TNF inhibitor [75,76].

In a randomized trial that compared ixekizumab with adalimumab, ixekizumab was superior for the primary outcome, which required improvement in both the peripheral arthritis and skin disease [39,77]. After 52 weeks of therapy, ixekizumab and adalimumab had similar efficacy for joint disease (American College of Rheumatology (ACR) criteria for 20 percent improvement [ACR20] (table 1) 70 versus 69 percent), but ixekizumab was superior to adalimumab in controlling the skin disease (patients achieving complete clearance of all cutaneous lesions, Psoriasis Area and Severity Index [PASI100]: 64 versus 41 percent).

Bimekizumab — Bimekizumab, a monoclonal antibody directed against both IL-17A and IL-17F, appears to be both safe and effective for the treatment of both psoriasis and PsA, even for patients who had previously failed therapy with TNF inhibition. Although there have not been comparative studies with other IL-17i for the treatment of PsA, the efficacy at the tested dose (160 mg) appears to be similar to the IL-17Ai. On the other hand, at the psoriasis dose (320 mg), the efficacy for bimekizumab was significantly greater than secukinumab (psoriasis dose 300 mg) for clearance of psoriasis (PASI100).

●BE OPTIMAL enrolled 852 patients with active PsA, who received treatment with either bimekizumab 160 mg every four weeks, adalimumab 40 mg every two weeks, or placebo [78]. After 16 weeks, patients treated with bimekizumab were more likely to achieve an ACR50 response than patients treated with placebo (43 versus 9 percent; OR 7.1, 95% CI 5.6-10.9). The ACR50 response was comparable among patients who received bimekizumab versus adalimumab (44 versus 47 percent). The PASI90 at week 16 was 61.3 percent in the bimekizumab group, 41.2 percent in the adalimumab group, and 2.9 percent in the placebo group.

●BE COMPLETE enrolled 400 patients with active PsA who had previously failed therapy with at least one TNF inhibitor (either due to intolerance or lack of response) [79]. After 16 weeks, patients treated with bimekizumab (160 mg every four weeks) were more likely to achieve an ACR50 response (44 versus 10 percent; adjusted OR 11.1, 95% CI 5.4-23.0).

●In an open-label extension phase of an earlier dose-ranging study (BE ACTIVE), the efficacy of bimekizumab appeared to be sustained over three years of follow-up [80-82]. In all of these studies, bimekizumab was well tolerated, and the overall safety profile was similar to that reported in previous studies of this agent.

FAILURE OF TNF AND IL-17 INHIBITION

Initial considerations — In patients without an adequate response to tumor necrosis factor (TNF) and interleukin 17 (IL-17) inhibitors, we consider the following:

●Is the diagnosis correct? Most patients will have some response to TNF or IL-17 inhibition, even if the response is inadequate.

●Is the patient adherent to the treatment plan?

●Does the patient have concomitant fibromyalgia or central sensitization that may be responsible for the continued symptoms?

●Are there other factors preventing the patient from responding (eg, depression, anxiety, obesity) that could be addressed separately?

Early identification of these issues may avoid inappropriate cycling through multiple immunosuppressive agents that are unlikely to benefit the patient.

If these issues have been excluded, and the patient requires ongoing immunosuppression, we select an agent based on the presence (or absence) of concomitant axial disease, as discussed below.

Patients without concomitant axial disease — For patients without concomitant axial disease, we suggest an IL-23 inhibitor such as guselkumab or risankizumab, both of which have been approved by the US Food and Drug Administration (FDA) for the treatment of psoriatic arthritis (PsA). For patients who cannot use an IL-23 inhibitor (eg, due to intolerance or lack of availability), ustekinumab is a reasonable choice. Abatacept is an option for patients who have a rheumatoid arthritis-like presentation (ie, minimal or no psoriasis and no axial disease).

These agents may be given with or without apremilast, methotrexate (MTX), leflunomide (LEF), or cyclosporine, which may be discontinued if a patient responds to the combination.

Guidelines for drug monitoring are discussed in the table (table 4).

Guselkumab — Guselkumab, which is effective for the treatment of moderate to severe psoriasis and for active PsA, is an anti-IL-23-specific monoclonal antibody that targets the p19-protein subunit of IL-23 [83].

●Dosing and administration – Guselkumab is administered by subcutaneous injection (100 mg, given initially and four weeks later, then every eight weeks).

●Efficacy – The efficacy and safety of guselkumab for PsA has been demonstrated in randomized trials, which have evaluated patients with active PsA, some of whom had failed to respond to TNF inhibition. Guselkumab may be particularly effective for patients who have active skin disease.

•In a randomized trial involving 149 patients with active PsA and plaque psoriasis, an American College of Rheumatology (ACR) criteria for 20 percent improvement (ACR20) (table 1) response at week 24 was achieved more frequently in the patients allocated to receive guselkumab compared with placebo (58 versus 18 percent) [84].

•The DISCOVER 1 trial enrolled 381 patients, most of whom were naïve to biologic agents (30 percent were TNF inhibitor-experienced patients), who were randomized to placebo or guselkumab every four or every eight weeks. At 24 weeks, the ACR20 was achieved by more patients who received guselkumab every four weeks (59 percent) or every eight weeks (52 percent) versus placebo (22 percent) [85].

•In the DISCOVER 2 trial, which enrolled 741 TNF inhibitor-naïve patients, ACR20 response occurred in more patients who received guselkumab (at either frequency) versus placebo (64 versus 33 percent) [86]. The drug provided sustained benefits across multiple disease domains through one year, and the rates of adverse events, including infection, were similar in the two groups [87].

•A systematic literature review suggested that guselkumab has better efficacy for the skin domain of PsA than multiple other agents, including TNF inhibitors, Janus kinase (JAK) inhibitors, and upadacitinib [88].

Risankizumab — Risankizumab, which is effective for the treatment of moderate to severe plaque psoriasis and for active PsA, is an anti-IL-23 antibody that targets the p19-protein subunit of IL-23.

●Dosing and administration – It is administered by subcutaneous injection (150 mg, given initially and four weeks later, then every 12 weeks).

●Efficacy – The efficacy and safety of risankizumab for PsA has been demonstrated in randomized trials that have evaluated patients with active PsA, some of whom had failed to respond to prior biologic therapy.

•In biologic-naïve patients – In the randomized KEEPsAKE 1 trial, 964 patients received risankizumab 150 mg or placebo at weeks 0, 4, and 16. At week 24, more risankizumab-treated patients achieved an ACR20 (table 1) response (57.3 versus 33.5 percent) [89]. Significantly higher responses were also achieved for skin and nail psoriasis, minimal disease activity (MDA), resolution of enthesitis and dactylitis, health-related quality of life, pain, and fatigue [90]. The drug was well tolerated.

•In patients with inadequate response to biologic therapies – KEEPsAKE 2 included 444 patients randomized to risankizumab or placebo. Patients with previous exposure to biologics (TNF inhibitors, cytotoxic lymphocyte-associated molecule-4-immunoglobulin [CTLA-4-Ig], or rituximab) were included with appropriate washout periods. At week 24, more risankizumab-treated patients achieved an ACR20 response (51.3 versus 26.5 percent). Other endpoints, including change in Health Assessment Questionnaire-Disability Index (HAQ-DI), Psoriasis Area and Severity Index (PASI) 90, MDA, and Functional Assessment of Chronic Illness Therapy–Fatigue Scale (FACIT-Fatigue), also demonstrated improvement with risankizumab [91].

Ustekinumab — Ustekinumab, which is used for the treatment of moderate to severe plaque psoriasis and active PsA, is a human monoclonal antibody to the shared p40 subunit of IL-12 and IL-23 that interferes with receptor binding to immune cells.

●Dosing and administration – Ustekinumab is administered by subcutaneous injection (45 mg, given initially and four weeks later, then every 12 weeks).

A higher dose of ustekinumab is used for patients with coexistent moderate to severe plaque psoriasis weighing greater than 100 kg (220 lbs; ie, 90 mg initially and four weeks later, followed by 90 mg every 12 weeks) [92].

More frequent dosing is used in patients with concomitant inflammatory bowel disease (ie, every eight weeks).

●Efficacy - The efficacy and safety of ustekinumab for PsA has been demonstrated in randomized trials that have evaluated patients with active PsA despite prior treatment [93-95]:

•In TNF-naïve patients – A trial randomized 615 patients with PsA to treatment with either ustekinumab (90 or 45 mg) or placebo every 12 weeks (following a loading dose); at week 16, patients who failed to respond underwent dose escalation [93].

At week 24, the ACR20 (table 1) was achieved significantly more often by the patients receiving ustekinumab (at either dose) compared with those receiving placebo (ACR20 46 versus 23 percent), and responses were maintained at week 52. Clinically and statistically significant improvement in function at week 24 was also achieved more often in the patients receiving ustekinumab at either dose (HAQ-DI increase of at least 0.3 in 48 versus 28 percent). Statistically significant improvements in psoriasis, dactylitis, and enthesitis were also noted.

•After TNF inhibitor failure – Patients with active PsA despite treatment with a TNF inhibitor were evaluated in another randomized trial with a similar design to that above (the PSUMMIT 2 trial). At week 24, an ACR20 was achieved significantly more often by the patients receiving ustekinumab (at either dose) compared with those receiving placebo (44 versus 20 percent) [95]. Benefits in composite measures of disease activity and function were sustained at week 52.

Serious adverse events occurred in 5.2 percent (15 of 287) of patients treated for 60 weeks with ustekinumab (11.82 per 100 patient-years). These included serious infections but no cases of tuberculosis and no deaths.

•Combined data from these trials also indicated that treatment with ustekinumab resulted in a statistically significant reduction of radiographic progression of joint injury compared with placebo from baseline to week 24 (modified Sharp-van der Heijde score increase of 0.4 versus 1.0) [96]. Inhibition of progression was maintained at week 52.

There are no clinical trials directly comparing ustekinumab with another therapy for peripheral arthritis in PsA. However, an observational study conducted in Europe suggests that ustekinumab and TNF inhibition have comparable results for patients with peripheral PsA [97]. Another study indicates that ustekinumab may be more effective than TNF inhibitors for enthestitis [98]. Coadministration with MTX does not seem to improve outcomes [99].

Abatacept — Abatacept (CTLA-4-Ig), which is used for the treatment of active PsA, is a selective T-cell costimulation modulator.

●Dosing and administration – It is administered subcutaneously (125 mg once weekly) or intravenously (given initially, two, and four weeks later, then every four weeks thereafter). When administered intravenously, the dose is weight based (500 mg for patients less than 60 kg; 750 mg for patients 60 to 100 kg; 1000 mg for patients greater than 100 kg).

●Efficacy – The efficacy and safety of abatacept for PsA has been demonstrated in randomized trials that have evaluated patients with active PsA.

•In a six-month study of 170 PsA patients who had previously been treated with immunosuppression (88 percent of whom had been treated with a TNF inhibitor), an ACR20 (table 1) was achieved by more patients treated with abatacept 10 mg/kg versus placebo (48 versus 19 percent) [100].

•In a six-month study of 424 PsA patients (60 percent of whom had been treated with a TNF inhibitor), an ACR20 was achieved by more patients treated with subcutaneous abatacept 125 mg weekly versus placebo (39 versus 22 percent) [101].

There was minimal effectiveness for psoriasis in this study. Thus, abatacept is not ideal for patient with bothersome skin disease.

Janus kinase inhibitor for patients with concomitant axial disease — For patients with concomitant axial disease, we suggest a JAK/signal transducer and activator of transcription (STAT) inhibitor such as tofacitinib or upadacitinib, both of which have been approved by the FDA for the treatment of PsA and had been shown to be also effective in axial spondyloarthritis, in contrast to IL-23 inhibitors ustekinumab and abatacept.

Precautions regarding the use of JAK inhibitors are discussed elsewhere. (See "Overview of the Janus kinase inhibitors for rheumatologic and other inflammatory disorders", section on 'Pretreatment screening and precautions' and "Overview of the Janus kinase inhibitors for rheumatologic and other inflammatory disorders", section on 'Adverse effects'.)

Tofacitinib — Tofacitinib, which is available for the treatment of active PsA that has had an inadequate response to TNF inhibition, is an oral inhibitor of JAK1 and JAK3.

●Dosing and administration – Tofacitinib is administered orally in combination with a nonbiologic oral immunosuppressant, such as MTX. The immediate release formulation is dosed at 5 mg twice daily. The extended release formulation is dosed at 11 mg daily.

●Efficacy – The efficacy and safety of tofacitinib for PsA has been demonstrated in randomized trials that have evaluated patients who have had an inadequate response to a conventional oral immunosuppressant [102] or TNF inhibitor therapy [103].

•In TNF-inhibitor naïve patients – The Oral Psoriatic Arthritis Trial [OPAL] Broaden enrolled 422 patients with active PsA who had an inadequate response to at least one conventional oral immunosuppressant but were TNF inhibitor-naïve. At three months, an ACR20 (table 1) was achieved by more patients treated with tofacitinib 5 mg twice daily (50 percent), tofacitinib 10 mg twice daily (61 percent), or adalimumab 40 mg subcutaneous every two weeks (52 percent) versus placebo (33 percent) [102]. Physical function was also improved at three months. Responses were maintained through month 12, and there were similar rates of serious adverse effects with either of the active drugs. Greater benefit with tofacitinib (5 or 10 mg twice daily) versus placebo was seen by week 2 (ACR20 of 22 and 32 versus 6 percent).

•In patients with inadequate response to TNF inhibition – In another randomized phase 3 trial (OPAL Beyond), involving 395 patients with active PsA and an inadequate response to a TNF inhibitor, treatment with tofacitinib (5 mg or 10 mg twice daily) resulted in greater benefit compared with placebo at three months (ACR20 of 50 and 47 versus 24 percent) [103]. Greater improvements in physical function at three months were also observed in the tofacitinib-treated patients. Responses were maintained through the six-month trial. Adverse effects with tofacitinib were similar to those seen in other trials in patients with rheumatoid arthritis or psoriasis.

Upadacitinib — Upadacitinib, which is available for the treatment of active PsA that has had an inadequate response to TNF inhibition, is an oral inhibitor of JAK1.

●Dosing and administration – Upadacitinib is administered orally (15 mg daily).

●Efficacy – The efficacy and safety of upadacitinib for PsA has been demonstrated in randomized trials that have evaluated patients with active PsA who have had an inadequate response to a conventional oral immunosuppressant [40] or TNF inhibitor therapy [104].

•In biologic-naïve patients – In the SELECT-PsA 1 trial, 1704 patients with PsA received upadacitinib 15 or 30 mg, placebo, or adalimumab 40 mg every two weeks [40]. The ACR20 (table 1) response at week 12 was highest in upadacitinib-treated patients (70.6 percent with the 15 mg dose and 78.5 percent with 30 mg dose) compared with adalimumab (65.0 percent) and placebo (36.2 percent). Upadacitinib (at either dose) was also more effective at improving function (ie, HAQ-DI). The percentage of patients who had 75 percent improvement in their skin lesions (ie, PASI75 response), MDA, and resolution of enthesitis, and improvement in the 36-Item Short Form Health Survey physical component summary score (SF-36 PCS) and FACIT-Fatigue scores was significantly higher among the patients taking upadacitinib versus placebo.

•In patients with inadequate response to at least one biologic agent – In the SELECT-PsA 2 trial, 641 patients were randomized to treatment with upadacitinib 15 or 30 mg orally or placebo [104]. More patients achieved an ACR20 response at week 12 with upadacitinib at either dose (56.9 and 63.8 versus 24.1 percent). At week 24, MDA was achieved by more upadacitinib 15 mg-treated (25.1 percent) and 30 mg-treated patients (25.1 and 28.9 versus 2.8 percent). Benefit was also noted for HAQ-DI, FACIT-Fatigue, and resolution of enthesitis.

ASSESSMENT OF TREATMENT RESPONSE — Typically, patients require up to three months to respond to therapy, but many respond sooner, as illustrated in multiple randomized trials with these drugs. Assessment of the treatment response should be individualized to incorporate other domains of disease activity in addition to arthritis, such as psoriatic skin involvement, dactylitis, and enthesitis, particularly in patients with moderate to severe involvement in these other domains. With respect to the musculoskeletal manifestations, a target of minimal disease activity (MDA) is desirable, but some patients will want to prioritize the treatment of other disease domains. (See "Treatment of psoriatic arthritis", section on 'Monitoring' and 'Initial considerations' above.)

Guidelines for drug monitoring are discussed in the table (table 4).

INVESTIGATIONAL TREATMENTS

●Combination therapy – For patients with severe and treatment-resistant disease, combination therapy may be an important option. However, there are inadequate data to support this approach routinely.

The AFFINITY Trial (NCT05071664) is comparing the combination of guselkumab and golimumab versus guselkumab monotherapy for the treatment of psoriatic arthritis (PsA), but data from this study are not yet available [105].

●Other interleukin-17 and interleukin-23 inhibitors

•Brodalumab – Brodalumab is an anti-interleukin 17 (IL-17) receptor antibody that is approved by the US Food and Drug Administration (FDA) for use in psoriasis and has shown efficacy in trials for PsA [106-113].

Two phase 3 trials tested the efficacy of brodalumab 140 or 210 mg subcutaneously versus placebo in a total of 962 patients with PsA [113]. Approximately 30 percent had received biologic agents.

In a pooled analysis at 16 weeks, American College of Rheumatology (ACR) criteria for 20 percent improvement (ACR20) (table 1) response rates were 45.8 and 47.9 versus 20.9 percent for 140 and 210 mg versus placebo-treated patients. ACR50 and ACR70 responses were also significantly higher among patients treated with either dose. Benefit was sustained through week 24.

Psoriasis Area and Severity Index (PASI) 100 responses (ie, complete resolution of the patient’s skin lesions) were achieved by 40.8 percent of the patients treated with 210 mg, 20.7 percent of those treated with 140 mg, and only 1.9 percent of the placebo-treated patients.

Adverse events were not different between the two brodalumab doses and placebo. However, brodalumab trials in PsA were stopped due to a relatively high rate of suicidal ideation and six completed suicides in clinical trials of brodalumab [114]. In the United States, brodalumab can be used for psoriasis after screening for suicidality and enrollment in a Risk Evaluation and Mitigation Strategy (REMS) program [115].

Tildrakizumab – Tildrakizumab is an anti-IL-23 p19 monoclonal antibody that is approved for the treatment of psoriasis [116]. Phase 3 trials in PsA are in progress (NCT04314544, NCT04314531).

●Other JAK/STAT and TYK2 pathway inhibitors

•Deucravacitinib – The tyrosine kinase 2 (Tyk2) inhibitor deucravacitinib was studied in a trial of 203 patients with PsA who were randomized to deucravacitinib 6 mg, 12 mg, or placebo [117]. Patients in both deucravacitinib treatment groups were more likely to experience improvement in their peripheral arthritis than patients who received placebo (53 versus 63 versus 32 percent). No serious adverse events were reported in this trial.

•Filgotinib – Filgotinib, a Janus kinase 1 (JAK1) inhibitor, is approved for the treatment of rheumatoid arthritis in Europe, but it was withdrawn from clinical trials in North America based on concerns regarding sperm toxicity in animals [118].

•Brepocitinib – Brepocitinib is a JAK1/TYK2 inhibitor that demonstrated benefit but at this time is not being further pursued [119]. Other TYK2 and JAK1/TYK2 inhibitors are under development.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Psoriatic arthritis in adults" and "Society guideline links: Spondyloarthritis".)

SUMMARY AND RECOMMENDATIONS

●Management of minimal peripheral arthritis – For patients with intermittent joint symptoms that do not significantly impact the patient’s activities, we suggest initiating treatment with symptomatic therapies such as a nonsteroidal antiinflammatory drug (NSAID) (Grade 2C). Options include naproxen 375 to 500 mg twice daily, celecoxib 200 mg twice daily, and meloxicam 15 mg daily (table 2).

NSAIDs can help control the mild inflammatory symptoms of psoriatic arthritis (PsA) and may also lessen pain and stiffness in associated spondylitis. A concern that NSAIDs may aggravate the skin psoriasis remains unproven. (See 'Minimal disease' above.)

●Management of mild peripheral arthritis – For patients with up to three active joints or intermittent joint involvement that has failed to respond to NSAIDs, we suggest treating with apremilast (Grade 2B). Methotrexate (MTX) is an appropriate alternative if apremilast is not available. (See 'Mild disease' above.)

●Management of moderate to severe disease – For patients with highly active disease (eg, multiple involved joints, erosive disease at presentation, functional limitation) and for patients who fail to improve with apremilast or MTX, we suggest treatment with a tumor necrosis factor (TNF) inhibitor (Grade 2C). TNF inhibitors have demonstrated efficacy in PsA. Other agents may be similarly effective; however, comparative efficacy trials are lacking.

The efficacy of all TNF inhibitors for PsA are comparable, and the choice of agent is largely determined by patient and payor preferences. (See 'Moderate to severe disease' above.)

●Failure of initial TNF inhibitor – For patients who experience loss of efficacy following an initial response to TNF inhibition, we suggest switching to another TNF inhibitor or to an interleukin 17 (IL-17) inhibitor (Grade 2C). (See 'Failure of initial TNF inhibitor' above.)

●Failure of TNF and IL-17 inhibition – For patients who have failed to respond to TNF and IL-17 inhibition, we suggest the following approach (see 'Patients without concomitant axial disease' above):

•For patients without concomitant axial disease – We suggest an IL-23 inhibitor (ie, guselkumab, risankizumab, or bimekizumab) (Grade 2C). For patients who cannot use an IL-23 inhibitor (eg., due to intolerance), ustekinumab is a reasonable choice. Abatacept can be used if the patient has minimal or no psoriasis.

•For patients with concomitant axial disease – We use a JAK inhibitor (eg, tofacitinib, upadacitinib).

●Assessment of treatment response – Patients may require up to three months to respond to therapy. Patient assessment should consider all of the domains of PsA (ie, peripheral arthritis, axial arthritis, dactylitis, enthesitis, skin, and nails). (See 'Assessment of treatment response' above.)

Guidelines for drug monitoring are discussed in the table (table 4).